Diagnosis of myelodysplastic syndrome among a cohort of 119 patients with fanconi anemia: morphologic and cytogenetic characteristics

Abstract

Predisposition to myelodysplastic syndrome (MDS) and acute leukemia is a hallmark of Fanconi anemia (FA). Morphologic criteria for MDS in FA are not well established, nor is the significance of clonal chromosomal abnormalities. We reviewed bone marrow samples of 119 FA patients: 23 had MDS, with the most common subtype refractory cytopenia with multilineage dysplasia. The presence of MDS was highly correlated with the presence of clonal abnormalities. Neutrophil dysplasia and increased blasts were always associated with the presence of a clone, in contrast with dyserythropoiesis. The most frequent clones had gains of 1q and 3q and/or loss of 7. Karyotype complexity also correlated with MDS. One third of patients with 3q as a sole abnormality had no MDS; patients with 3q and an additional abnormality all had MDS. The data provide a rationale for integrating cytogenetic findings with independently evaluated morphologic findings for monitoring bone marrow status in FA.

Figure 1

Relationship between different morphologic parameters and the presence of a clonal abnormality in Fanconi anemia (FA). The most reliable morphologic criteria for a diagnosis of myelodysplastic syndrome in FA are increased blasts and dysgranulopoiesis (DysGran), followed by dysmegakaryopoiesis (DysMeg) and increased ringed sideroblasts (Rings). Dyserythropoiesis (DysEryth) does not correlate with the presence of clonal abnormalities.

Image 1

Morphologic abnormalities identified in the bone marrow of patients with Fanconi anemia. A, Rare erythroid precursor with irregular nucleus in non–myelodysplastic syndrome (MDS). B, Rare hypogranular neutrophil and rare megakaryocyte with nonlobated nucleus in borderline MDS. C, Pseudo–Pelger-Huët neutrophil and megaloblastic erythroid precursor with irregular nucleus in refractory cytopenia with multilineage dysplasia (RCMD). D, Numerous small bilobed megakaryocytes in RCMD. E, Increased ringed sideroblasts in refractory anemia with ringed sideroblasts. F, Increased blasts in refractory anemia with excess blasts-1 (A, B, C, E, and F, Wright-Giemsa, ×2,000; D, H&E, ×1,000).

Image 2

A, 3qG presenting as part of a derivative chromosome. Left panel, G-banding demonstrates additional material added to the short arm of chromosome 16. Right panel, Fluorescence in situ hybridization (FISH) with a whole chromosome 3 paint probe shows hybridization to the 2 normal No. 3 chromosomes and to the short arm of the abnormal chromosome 16. The abnormal chromosome 16 is designated as der(16)t(3;16)(q25;p13.3). B, G-banding, M-FISH, and array comparative genomic hybridization (CGH) resolve a complex karyotype with 3qG. Left panel, G-banding reveals gain of 2 extra copies of chromosome 1q resulting from a supernumerary t(1;1), an abnormal chromosome 18 with material of unknown origin added to its distal long arm, and a small supernumerary chromosome. Middle panel, Multicolor FISH confirms the gain of chromosome 1q material and further shows that the material added to chromosome 18 is derived from chromosome 9, and the small supernumerary chromosome is derived from chromosome 3. Right panel, CGH reveals the region of 3q in the marker extends frp, 3q21 to the 3q telomere (2 extra copies of this region are present).